Chiral synthesis for producing 1-azabicyclo(2.2.1)heptane-3-carboxylates

ABSTRACT

A process for preparing substantially pure enantiomers of formula (I) ##STR1## where the * represents a chiral center, x is 0 or 1, in exo-, endo- or a mixture of exo- and endo- forms; and R is hydrogen, alkyl or aralkyl, via diastereomers of formula (IIA) or (IIB): ##STR2##

This is a division of application Ser. No. 520,945, filed May 9, 1990now U.S. Pat. No. 5,104,989.

The present invention relates to a process for resolving enantiomers ofcompounds useful as intermediates in the synthesis of oxadiazoles havingmuscarinic agonist activity.

In European published patent specifications nos. 239309, 257741 and261763 are disclosed certain azabicyclic compounds, including oxadiazolederivatives thereof, having for example, muscarinic agonist activity andprocesses for their preparation. The processes disclosed are multi-stepand include those which proceed via intermediates of formula (A)##STR3## including analogues and derivative thereof. Both the finalazabicyclic compounds and the intermediates of formula (A) have at leastone asymmetric centre and can therefore exist as both enantiomers anddiastereomers. Some, such as the intermediate of formula (A), can existas exo- and endo-isomers. However, no process is disclosed wherein theoptical isomers of the final azabicyclic compounds (nor theintermediates of formula (A) nor its analogues and derivatives) canseparately be prepared or the racemic mixture resolved.

Thus, in order to prepare individual enantiomers of the oxadiazolesmentioned above and other substituted azabicycles, attempts were made toresolve optically active intermediates used in their preparation.Various of the conventional methods were tried, but without completesuccess. For example, it was found that using chiral acids such astartaric and camphor-10- sulphonic was unsuccessful. Likewise, the useof chiral esters such as derivatives of menthol,N-benzoyl-2-amino-1-butanol and N-benzoyl norephedrine did not work aseither they could not be prepared or the chiral derivatives of theazabicycles would not separate. It was then surprising to find that achiral amide of an intermediate could be prepared and could give rise toseparation of the enantiomers, as desired.

The present invention is based on a novel intermediate of formula IIhaving a removable N-substituent which possesses a chiral centre andprovides a precursor for preparing a substantially pure enantiomer of a1-azabicyclo[2.2.1]heptane or a 1-azabicyclo[3.2.1]octane substituted onthe carbon atom β to the ring nitrogen by a carboxylic acid ester group.The diastereomers may be separated before continuing with the synthesis.

EP261763 describes a N-protected tetrahydropyrrole, which is cyclised togive a azabicyclo[2.2.1]heptane-3-carboxylic acid. However, theN-protecting group did not possess a chiral centre and there was nosuggestion that the compound could be employed as a means of separatingdiastereomers at that stage.

The present process has the advantages of producing diastereomers ofoptically active intermediates which are capable of separation bystandard means at more than one stage in their preparation and which, inseveral cases, are in crystalline form.

In particular, the present invention provides a process for preparingsubstantially pure enantiomers of formula (I) ##STR4## where the *represents a chiral centre, x is 0 or 1, in exo-, endo- or a mixture ofexo- and endo- forms; and R is hydrogen, alkyl or aralkyl which processcomprises:

(a) synthesising diastereomers of formula (IIA) or (IIB): ##STR5##wherein R¹, R² and R³ are each selected from H, alkyl, aryl and aralkyl,provided that R¹, R² and R³ are each different from each other; R and xare as defined in formula (I); and Y is a leaving group;

(b) cyclising the diastereomer of formula IIA or IIB to thecorresponding diastereomer of formula (III) ##STR6## wherein R to R³ areas in formula (I) and M is a counter ion;

(c) separating the diastereomers formed at step (a) or step (b);

(d) hydrogenation of the diastereomer of formula (III) to give thecorresponding substantially pure enantiomer of formula (I); and

optionally converting the enantiomer of formula (I) to a reactivederivative thereof.

R¹, R² and R³ may be suitably selected from H, C₁₋₄ alkyl, phenyl,naphthyl and benzyl.

The preferred process is one wherein, in formula (II), R¹ is H, R² ismethyl and R³ is phenyl or naphthyl, preferably phenyl. Preferably R isC₁₋₄ alkyl or benzyl, in particular ethyl. Suitable leaving groups Yinclude bromo, and acetoxy.

The cyclisation step (b) (compound IIA or IIB to compound III) may becarried out using an alcohol, R--OH to produce compound III wherein R isalkyl or aralkyl; or using acetic acid to produce compound III where Ris hydrogen. R-OH may be, for example, a lower alkanol having two ormore carbon atoms optionally aryl substituted, such as ethanol, propanolor butanol. Preferably ROH is ethanol, propanol or butanol, especiallyethanol.

The cyclisation is effected in the presence of an agent which willgenerate a cation at the carbon atom β to the ring carbonyl but whichwill not complex with the ring nitrogen, such as a hydrogen halide (e.g.HI, HBr). Preferably, HBr is used.

It is possible to separate the diastereomers of formula IIA/IIB or thoseof formula III. It is usually preferable to separate at the latterstage, as formula III is a quaternary salt, the diastereomers of whichare more readily separable by means of fractional crystallisation. Anyother separation technique may be used, for example chromatography.

The hydrogenation step (c) may be effected by hydrogen and a catalystsuch as platinum or palladium or carbon, for example 5% or 10% palladiumon carbon. Alternative methods such as transfer methods may also beemployed such as using cyclohexene and an alcohol such as ethanol with acatalyst such as those mentioned above.

The final product enantiomers of formula (I) may be isolated in saltform such as the oxalate, maleate or hydrochloride salts. Once formed,the product enantiomers of formula (I) may, optionally be racemised to amixture of the exo+endo isomers by, for example, base catalysedequilibration, or they may be used in the process described in ourco-pending UK patent application no. 89110811.

Compounds of formula III and I, where R is alkyl or benzyl, may behydrolysed to the corresponding compound where R is hydrogen. Compoundsof formula I where R is hydrogen may be converted to any other reactivederivative thereof, such as the acid halide or anhydride, especially theacid chloride.

The process of this invention is therefore able to produce an enantiomerof formula I where CO₂ R represents a carboxylic acid group or areactive derivative thereof.

Synthesis of the compound of formula (II) may be effected by reacting apyranone of formula ##STR7## wherein x is as defined in formula (I) withan optically active aminoacetal of formula (IV): ##STR8## wherein R¹ toR³ are as defined in formula (II) and R⁴ is C₁₋₆ alkyl or aryl (i.e. asubstituent which cleaves on addition of the pyranone). Preferredsubstituents for R¹ to R³ are as hereinbefore described for formula(III); R⁴ is preferably methyl, propyl or butyl, more preferably methyl.The process is preferably carried out using the (+) optical isomer.Reaction of the pyranone with the optically active acetal of formula(IV) is effected optionally in the presence of an acid catalyst such ascamphor sulphonic acid or preferably, trifluoroacetic acid.

Preparation of the optically active acetal (IV) is by methods analogousto those published in the art; for example, from an optically activesilyl amine of formula (V): ##STR9## wherein R¹ to R³ are as defined informula (II), by reaction with R⁴ OH wherein R⁴ is as defined in formula(IV) in the presence of an agent such as aqueous formaldehyde.

The optically active silyl amine (V) may itself be prepared by reactingan optically active amine of formula (VI) ##STR10## wherein R¹ to R³ areas defined in formula (II) with a silyl compound of formula Me₃ Si--CH₂--X (wherein X is halo such as chloro) by methods analogous to thosepublished in the art. The preferred optically active amine isR-(+)-α-methylbenzylamine.

The present invention further provides novel isomers of formulae (V),(IV), (II), (III) and (I) as hereinbefore defined. In addition,operating the process wherein, in formula (V), R is H provides a usefulmethod of preparing non-chiral analogues of the compounds of formulae(II) and (IV).

The present invention will now be illustrated by the following examples,although other ways of putting it into effect will be clear from theforegoing description to the person skilled in the art.

EXAMPLE 1 (S)-(-)-N-1-(1-Naphthylethyl-N-trimethylsilylmethylamine (V,R¹ =H, R² =Me, R³ =1-naphthyl)

(S)-(-)-1-(1-Naphthyl)ethylamine (12.5 g, 0.073 moles) andchloromethyltrimethylsilane (6.0 g, 0.049 moles) were gently heatedtogether under reflux (ca. 105° C.) and under a nitrogen atmosphere.Heating was continued for 4 hours, the oil bath temperature reaching185° C. The reaction mixture was cooled in a water bath, toluene (50 ml)added and the mixture made strongly basic by the addition of 15%potassium hydroxide solution (45 ml). The mixture was stirredvigorously, the layers separated and the aqueous layer extracted withtoluene (2×50 ml). The organic phases were combined, dried (K₂ CO₃) andevaporated under reduced pressure to an orange oil. Chromatography ofthe oil on silica gel with ethyl acetate followed by distillation(Kugelrohr) gave the amine as a colourless oil (8.4 g, 67%) b.p. 100°C./0.3 mbar (Found: C, 74.68; H, 9.05; N, 5.40. (C₁₆ H₂₃ NSi requires C,74.65; H, 9.00; N, 5.44%).

EXAMPLE 2(R)-(+)-N-1-Phenylethyl-N-(methoxymethyl)trimethylsilylmethylamine (IV,R¹ =H, R² =R⁴ =Me, R³ =Ph)

(R)-(+)-N-1-Phenylethyl-N-trimethylsilylmethylamine (Padwa et al,Tetrahedron, 41,3529-3535 at p. 3532) (1.25 kg, 6.04 moles) was added toan ice-cooled mixture of methanol (232 g, 7.25 moles) and aqueousformaldehyde (37-40% w/w, 530 ml) over 30 minutes. The heterogeneousmixture was stirred at 0° C. for 2 hours then anhydrous potassiumcarbonate (240 g) was added and the mixture stirred for 30 minutes at 0°C. The layers were separated and the aqueous phase extracted withdiethyl ether (2.5 l). The organic phases were dried (Na₂ SO₄) andevaporated under reduced pressure at ≦30° C. to give the crude acetal(80% pure) as a colourless oil (1.46 kg, 96%)δ_(C) (CD₂ Cl₂)--1.1(SiMe₃), 19.61 (CMe), 40.38 (NCH₂ Si), 54.91 (OMe), 62.51 (CH), 86.41(NCH₂ O), 127.13, 128.16, 128.61, 146.07 (Ph).

EXAMPLE 3(S)-(-)-N-1-Phenylethyl-N-(butoxymethyl)trimethylsilylmethylamine (IV,R¹ =H, R² =Me, R³ =Ph, R⁴ =Bu)

The title compound was prepared from(S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction withn-butanol and aqueous formaldehyde following the procedure of Example 2to give the crude acetal (85% pure) as a colourless oil (7.1 g,80%)δ_(C) (CD₂ Cl₂)--1.09 (SiMe₃), 14.35, 20.16, 24.72, 67.38 (OBu),19.57 (CMe), 40.30 (NCH₂ Si), 62.30 (CH), 84.73 (NCH₂ O), 127.01,128.15, 128.51, 146.15 (Ph).

EXAMPLE 4(R)-(+)-N-1-Phenylethyl-N-(butoxymethyl)trimethylsilylmethylamine (IV,R¹ =H, R² =Me, R³ =Ph, R⁴ =Bu)

The title compound was prepared from(R)-(+)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction withn-butanol and aqueous formaldehyde following the procedure of Example 2to give the crude acetal (85% pure) as a colourless oil (34.2 g, 84%).The nmr spectrum was identical to the above (S)-isomer.

EXAMPLE 5 (S)-(-)-N-1-Phenylethyl-N-(octyloxymethyl)trimethylsilylmethylamine (IV, R¹ =H, R² =Me, R³ =Ph, R⁴ =Octyl)

The title compound was prepared from(S)-(-)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction withn-octanol and aqueous formaldehyde following the procedure of Example 2to give the crude acetal (90% pure) as a colourless oil (9.1 g,91%)δ_(C) (CD₂ Cl₂)--1.28 (SiMe₃), 14.29, 23.08, 30.31, 29.74, 29.89,26.82, 33.32, 63.13 (O Octyl), 19.37 (CMe), 40.11 (NCH₂ Si), 62.10 (CH),84.69 (NCH₂ O), 126.82, 127.96, 128.31, 145.95 (Ph).

EXAMPLE 6(S)-(-)-N-[1-(1-Naphthyl)ethyl]-N-methoxymethyltrimethylsilylmethylamine(IV, R¹ =H, R² =R⁴ =Me, R³ =1-naphthyl)

The title compound was prepared from(S)-(-)-N-1-(1-naphthyl)ethyl-N-trimethylsilylmethylamine by reactionwith methanol and aqueous formaldehyde following the procedure ofExample 2 to give the crude acetal (85% pure) as a colourless oil (3.6g, 93%)δ_(H) [(CD₃)₂ CO] 0.0 (s, SiMe₃), 1.57 (d, J 7 Hz, CMe), 2.18,2.40 (AB quartet, J 15 Hz, NCH₂ Si), 3.17 (s, OMe), 4.15, 4.30 (ABquartet, J 10 Hz, NCH₂ O), 4.72 (q, J 7 Hz, CH), 7.4-8.5 (m, naphthyl).

EXAMPLE 7(S)-(-)-N-[1-(1-Naphthyl)ethyl]-N-butoxymethyltrimethylsilylmethyl amine(IV, R¹ =H, R² =Me, R³ =1-naphthyl, R⁴ =Bu)

The title compound was prepared from(S)-(-)-N-1-(1-naphthyl)ethyl-N-trimethylsilylmethylamine by reactionwith n-butanol and aqueous formaldehyde following the procedure ofExample 2 to give the crude acetal (80% pure) as a pale yellow oil (5.5g, 82%)δ_(H) [CD₃)₂ CO] 0.1 (s, SiMe₃), 0.93 (t, J 7 Hz, CH₃ CH₂),1.2-1.7 (m, CH₃ CH and (CH₂)₂), 2.22, 2.45 (AB quartet, J 15 Hz, NCH₂Si), 3.25 (t, J 7 Hz, CH₂ O), 4.22, 4.35 (AB quartet, J 10 Hz, NCH₂ O),4.78 (q, J 7 Hz, CH), 7.3-8.5 (m, naphthyl).

EXAMPLE 82-[(R)-1-Phenylethyl]-4-oxo-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrrole(IIA, R¹ =H, R² =Me, R³ =Ph, x=zero-two diasteromers)

(a) Crude(R)-(+)-N-1-phenylethyl-N-(methoxymethyl)trimethylsilylmethylamine (265g, 0.84 moles) was added over 30 minutes to an ice-cooled, stirredsolution of 5.6-dihydro-2H-pyran-2-one (100 g, 1.02 moles) andtrifluoroacetic acid (0.5 ml) in ethyl acetate (1 l). The cooling bathwas removed and an exotherm carried the reaction temperature to 60° C.The solution was stirred for 1 hour at 50°-60° C. then cooled to 20° C.Aqueous sodium bicarbonate (240 ml) was added and the layers separated.The aqueous phase was back extracted with ethyl acetate (2×250 ml) andthe extracts combined, washed with water (100 ml), and dried (Na₂ SO₄).The solvent was removed under reduced pressure and the residue dissolvedin hot ethyl acetate (740 ml). A solution of maleic acid (118 g, 1.02mole) in hot ethyl acetate (1.3 l) was added with stirring. Hexane (370ml) was then added and the mixture seeded and allowed to cool. Theslurry was aged at 5° C. for 1 hour then filtered and washed with ethylacetate-hexane (5:1, 350 ml). The product was dried in vacuo to give themaleate salt as a colourless crystalline solid (288 g, 95%), m.p.123°-125° C. The nmr spectrum showed the product to be a 1:1 mixture ofcis diastereomers. The maleate salt (288 g) was added portionwise to astirred mixture of ethyl acetate (1.25 l) and aqueous sodium bicarbonate(1.75 l). The mixture was stirred at 20° C. for a further 30 minutesthen the layers were separated. The aqueous layer was extracted withethyl acetate (1 l×2), the organic layers combined and dried (Na₂ SO₄).The solution was evaporated under reduced pressure to afford the mixtureof diastereomers as a yellow oil (195 g, 100% recovery). GC (12 m OV-1column, 75° C. for 2 minutes then to 300° C. at 10° C./minute) Rt 16.1minutes 99.4 area %.

(b) Similarly reaction of(R)-(+)-N-(1-phenylethyl-N-butoxymethyltrimethylsilylmethylamine with5,6-dihydro-2H-pyran-2-one in the presence of trifluoroacetic acid gavethe lactone (18.5 g, 72% yield) with a nmr spectrum identical to theabove free base.

Separation of diastereomeric lactones

A 1:1 mixture of the diastereomers (10.9 g) was crystallised fromdiethyl ether (30 ml). The product was dissolved in boiling diethylether (40 ml) and the hot solution concentrated to ˜10 ml. The solutionwas allowed to cool and crystallise at 5° C. overnight. The product wascollected by filtration, washed with cold diethyl ether (2×5 ml) anddried in vacuo to give the more polar diastereomer2-[(S)-1-phenylethyl]-4-oxo-(3aR,7aS)-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrrole as a colourless solid(2.2 g, 41%) m.p. 86°-87° C. (Found: C, 73.34; H, 7.80; N, 5.65. ^(C)15^(H) 19NO² requires C, 73.44; H, 7.81; N, 5.71%) δ^(C) [(CD³)²CO]23.53 (7-CH²), 27.53 (Me), 35.64 (7a-CH), 42.65 (3a-CH), 56.30(1-CH₂), 59.82 (3-CH₂), 65.50 (CH), 67.61 (6-CH₂), 127.74, 129.17, 146.5(Ph), 173.42 (CO).

The crystallisation liquors were evaporated to an oil and preparativeHPLC (25 cm×21.2 mm Zorbax Sil column) with ethyl acetate gave the lesspolar diastereomer2-[(S)-1-phenylethyl]-4-oxo-(3S,7aR)-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrroleas an oil (2.1 g, 40%). δ_(C) [(CD₃)₂ CO]23.70 (7-CH₂), 27.70 (Me),35.76 (7a-CH), 42.67 (3a-CH), 58.86 (1-CH₂), 59.79 (3-CH₂), 65.59 (CH),67.68 (6-CH₂), 127.83, 129.24, 146.5 (Ph), 173.40 (CO). A sample of thebase was converted into the maleate salt m.p. 137°-139° C.

EXAMPLE 92-((S)-(-)-1-(1-Naphthyl)ethyl-4-oxo-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrrole(IIA, R¹ =H, R² =Me, R³ =1-naphthyl, x=zero)

(a) A 1M solution of trifluoroacetic acid in dichloromethane (1 ml) wasadded to a stirred solution of crude(S)-(-)-N-[1-(1-naphthyl)ethyl]-N-methoxymethyltrimethylsilylmethylamine(3.5 g, 9.9 mmol) and 5,6-dihydro-2H-pyran-2-one (1.3 g, 13.3 mmol) indichloromethane (15 ml) at 0° C. The cooling bath was removed and aslight exotherm was noted. After 20 minutes no acetal remained. Thereaction mixture was washed with saturated aqueous sodium bicarbonate(10 ml) and the aqueous solution back-extracted with dichloromethane(2×10 ml). The combined extracts were washed with saturated brine (10ml). dried (Na₂ SO₄) and evaporated under reduced pressure to give anorange oil. Chromatography on silica with ethyl acetate followed byKugelrohr distillation gave the lactone as an oil (2.2 g, 76%) b.p. 70°C./0.2 mbar. δ_(C) [(CD₃)₂ CO]22.72 (7-CH₂), 27.70 (Me), 35.84, 36.93(7a-CH), 42.74, 42.84 (3a-CH), 56.97, 57.08 (1-CH₂), 59.83, 60.06(3-CH₂), 67.70 (6-CH₂), 124.90, 125.09, 125.37, 125.80, 126.22, 126.55,128.19, 128.29, 129.22, 129.75, 147.80 (naphthyl).

The lactone (1.8 g, 6.1 mmol) was dissolved in t-butylmethylether (18ml) and treated with maleic acid (0.7 g, 6.0 mmol) in ethyl acetate (7ml). The crystalline product was filtered off, washed witht-butylmethylether (5 ml) and dried in vacuo to give the maleate salt(1.9 g, 76% recovery) m.p. 87°-98° C. (Found: C, 67.02; H, 6.6; N, 3.39.C₁₉ H₂₁ NO₂.C₄ H₄ O₄ requires C, 67.14; H, 6.12; N, 3.4%).

(b) Similarly reaction of(S)-(-)-N-[1-(1-naphthyl)ethyl]-N-butoxymethyltrimethylsilylmethylaminewith 5,6-dihydro-2H-pyran-2-one in the presence of trifluoroacetic acidgave the lactone (2.2 g, 59%) with a nmr spectrum identical to the aboveproduct.

EXAMPLE 10Cis-3-(2-Acetoxyethyl)-4-methoxycarbonyl-1-[(S)-1-phenylethyl]-pyrrolidine(IIB, R=Me, Y=MeCOO)

Potassium hydroxide (3.36 g, 60 mmoles) was added to a stirred solutionof 5,6-dihydro-2H-pyran-2-one (4.9 g, 50 mmoles) in water (45 ml) at 5°C. The solution was allowed to warm to 20° C. and stirred for 21/2 hoursthen evaporated to residue in a vacuum. The residue was flushed withisopropanol (2×50 ml) and dried in a vacuum at 50° C. over P₂ O₅. Thissolid was slurried in dry dimethylformamide (30 ml) and methyl iodide(34.2 g, 240 mmol) added. The slurry was stirred for 18 hours at 20° C.then quenched by the addition of ice (20 g). The mixture was extractedwith diethyl ether (4×50 ml) and the extracts washed with aqueous sodiumchloride (50 ml) and dried (Na₂ SO₄). Solvent removal in a vacuumafforded methyl (Z)-5-hydroxy-2-pentenoate as a colourless oil (4.1 g,63% yield). The oil was dissolved in dichloromethane (40 ml) withN,N-dimethylaminopyridine (0.1 g) and treated with acetyl chloride (2.75g, 35 mmoles) in dichloromethane (10 ml) added over 5 minutes at 5° C.The resulting slurry was allowed to warm to room temperature thenquenched by the addition of water (40 ml) and the layers separated. Theaqueous layer was extracted with dichloromethane (40 ml) and the organicextracts combined, washed with hydrochloric acid (0.5M, 2×50 ml) thenwater (2×50 ml), and dried (^(Na) 2SO⁴). Solvent removal in a vacuumfollowed by Kugelrohr distillation afforded methyl(Z)-5-acetoxy-2-pentenoate as a colourless oil (4.1 g, 76%) b.p. 75°C./0.1 mbar (Found: C, 55.60, H, 7.00 C₈ H₁₂ O₄ requires C, 55.80; H,7.00%).

A solution of the crude(S)-(-)-N-1-phenylethyl-N-(butoxymethyl)trimethylsilylmethylamine (2.90g) in dichloromethane (10 ml) was added to a solution of theacetoxy-ester (2.0 g, 11.6 mmoles) and trifluoroacetic acid (0.1 ml) indichloromethane (20 ml). After 18 hours at room temperature aqueoussodium bicarbonate (25 ml) was added and the layers separated. Theorganic layer was dried (Na₂ SO₄), evaporated to residue and the residuechromatographed on silica gel eluting with hexane-ethyl acetate (1:1).The early fractions gave the less polar isomer as an oil (0.75 g, 25%yield)δ_(C) [(CD₃)₂ CO] 20.80 (MeCO), 23.83 (Me), 29.80 (CH₂), 38.72(3-CH), 46.46 (4-CH), 51.54 (MeO), 55.83 (2-CH₂), 57.97 (5-CH₂), 63.57(CH₂ O), 65.92 (NCH), 127.64, 127.82, 129.32, 146.85 (Ph), 170.91 (CO),174.47 (CO).

Later fractions gave the more polar isomer as an oil (0.63 g, 22%yield)δ_(C) [(CD₃)₂ CO] 20.58 (MeCO), 23.39 (Me), 29.37 (CH₂), 38.38(3-CH₂), 46.36 (4-CH), 51.42 (MeO), 54.89 (2-CH₂), 58.59 (5-CH₂), 63.36(CH₂ O), 65.68 (NCH), 127.49, 127.65, 128.94, 146.0 (Ph), 171.0 (CO),1740 (CO).

Other fractions gave a mixture of isomers as an oil (0.57 g, 20% yield).

EXAMPLE 11 Ethyl 1-azoniabicyclo[2.2.1]heptane-3-carboxylate esters(III, R=Et, R¹ =H, R² =Me, R³ =Ph, x=zero, M⁻ =Br⁻)

(a) Ethyl1-[(S)-1-phenylethyl]-(3R,4S)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide

The "more polar"2-[(S)-1-phenylethyl]-4-oxo-(3aR,7aS)-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrrole(3.30 g, 13.5 mmoles) was dissolved in absolute ethanol (180 ml) and theclear solution saturated with anhydrous hydrogen bromide gas. Thesolution was heated at reflux temperature for 4 hours, then cooled andevaporated to residue under reduced pressure to give the bromoethylpyrrolidine (VII, R=Et, X=Br) as the hydrobromide salt. The residue wascooled in an ice-bath and basified by cautious addition of saturatedaqueous sodium bicarbonate. The product was extracted into chloroform(3×100 ml), dried (Na₂ SO₄), and the solvent removed under reducedpressure. The gummy residue was flushed with ethanol (3×100 ml) to givethe quaternary salt as a colourless crystalline solid (4.8 g, 100%)δ_(C)[(CD₃)₂ CO] 16.15, 62.09 (CH₃ CH₂ O), 14.41 (Me), 24.80 (5-CH₂), 38.87(4-CH), 43.19 (3-CH), 57.89 (2-CH₂), 59.94 (6-CH₂), 66.29 (CHN⁺), 66.61(7-CH₂), 129.27, 130.75, 130.84 (Ph).

(b) Ethyl1-[(S)-1-phenylethyl]-(3S,4R)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide

Similarly, the less polar (3aS,7aR) lactone (1.8 g, 7 mmoles) in ethanolsaturated with hydrogen bromide gave the quaternary salt (2.5 g,96%)δ_(C) (CD₂ Cl₂) 12.62, 60.39 (CH₃ CH₂ O), 14.78 (Me), 23.39 (5-CH₂),37.06 (4-CH), 42.94 (3-CH), 55.39 (2-CH₂), 58.85 (6-CH₂), 64.29 (CHN⁺),64.48 (7-CH₂), 127.85, 128.45, 128.88, 132.63 (Ph), 166.78 (CO).

(c) Ethyl1-[(R)-1-phenylethyl]-(3S,4R)-1-azoniabicyclo2.2.1]heptane-3-carboxylatebromide

Similarly a 1:1 mixture of2-[(R)-1-phenylethyl]-4-oxo-(3aR,7aS)-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrroleand the (3aS,7aR)-isomer (139 g, 0.57 moles) in ethanol (1.39 l)saturated with hydrogen bromide gave a mixture of the (3S,4R) and(3R,4S) quaternary salts (189 g) in 94% yield. The crude mixture wasdissolved in boiling ethanol (90 ml), and ethyl acetate (810 ml) addedto the hot solution. Cooling gave a crystalline solid (69.0 g) which wassuspended in boiling acetone (640 ml) for 1 hr. The suspension wascooled to 5° C. for 2 hrs, then filtered to give the (3S,4R) quaternarysalt as a colourless solid (64.0 g, 32%) m.p. 160°-161° C., [α]_(D) +21°(c 0.5 in EtOH).

(d) Ethyl1-[(S)-1-phenylethyl]-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide, as a mixture of (3R,4S) and (3S,4R) isomers, from acetoxyethylpyrrolidine (VII)

Cis-3-(2-Acetoxyethyl)-4-methoxycarbonyl-1-[(S)-1-phenylethyl]-pyrrolidine(0.5 g) in ethanol (25 ml) saturated with hydrogen bromide gave themixture of quaternary salts (0.55 g) in quantitative yield.

EXAMPLE 12 Propyl1-[(R)-1-phenylethyl]-(3S,4R)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide (III, R=Pr, R¹ =H, R² =Me, R³ =Ph, x=zero, M⁻ =Br⁻)

A solution of2-[(R)-1-phenylethyl]-4-oxo-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrroleisomers (5.8 g) in n-propanol (116 ml) was saturated with hydrogenbromide gas and heated under reflux overnight. The solvent was removedin vacuo and the residue treated with saturated aqueous sodiumbicarbonate (150 ml). The mixture was extracted with chloroform (3×100ml), dried (Na₂ SO₄), and evaporated to residue in vacuo.Crystallisation from acetone-ethyl acetate (1:1) afforded a 4:1diastereomeric mixture (3S,4R:3R,4S) of the quaternary salts.Recrystallisation from acetone (9 mlg⁻¹) afforded the pure (3S,4R)isomer as a colourless crystalline solid (1.3 g, 30%) m.p. 144°-146° C.δ_(C) (CD₂ Cl₂) 10.48, 22.25, 66.56 (CH₃ CH₂ CH₂ O), 16.45 (Me), 24.83(5-CH₂), 38.66 (4-CH), 45.12 (3-CH), 57.91 (2-CH.sub. 2), 59.70 (6-CH₂),66.36 (CHN⁺), 67.75 (7-CH₂), 129.70, 130.41, 130.78, 132.21 (Ph), 170.90(CO), [α]_(D) +22.6° (c 0.5 in EtOH).

EXAMPLE 13 Butyl1-[(R)-1-phenylethyl]-(3S,4R)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide (III, R=Bu, R¹ =H, R² =Me, R³ =Ph, x=zero, M⁻ =Br⁻)

A solution of2-[(R)-1-phenylethyl]-4-oxo-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrroleisomers (5.0 g) in n-butanol (100 ml) was saturated with hydrogenbromide gas and heated under reflux overnight. The solvent was removedin vacuo and the residue treated with aqueous sodium bicarbonate (150ml) and extracted with chloroform (3×100 ml). The extract was dried (Na₂SO₄) and evaporated to residue in vacuo. The crude product waschromatographed on silica gel eluting with ethyl acetate-methanol (3:1)then crystallised from ethyl acetate-acetone (4:1) to give the (3S,4R)salt as a colourless solid (1.06 g, 27%). m.p. 92°-94° C. δ_(C) (CD₂Cl₂) 13.81, 19.45, 30.69, 66.08 (CH₃ CH₂ CH₂ CH₂ O), 16.42 (Me), 24.83(5-CH₂), 38.62 (4-CH), 45.17 (3-CH), 57.86 (2-CH₂), 59.75 (6-CH₂), 66.22(CHN⁺), 66.52 (7-CH₂), 129.67, 130.36, 130.76, 134.15 (Ph), 170.81 (CO),[α]_(D) +22.9° (c 0.5 in EtOH).

EXAMPLE 14 Ethyl1-[(S)-1-Naphthylethyl]-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide (III, R=Et, R¹ =H, R² =Me, R³ =1-naphthyl, x=zero, M⁻ =Br⁻)

2-[(S)-1-(1-Naphthyl)ethyl]-4-oxo-1,2,3,6,7,7a-hexahydropyrano[3,4-c]pyrrole(3.8 g, 12.9 mmol) was dissolved in absolute ethanol (114 ml) and thesolution saturated with anhydrous hydrogen bromide (60 g). An exothermcarried the temperature to reflux. The mixture was heated under refluxfor 15 hours after which time tlc (alumina, MeOH-EtOAc, (1:1), l₂)indicated no starting material remained. The mixture was cooled andevaporated to residue under reduced pressure (temp. <40° C.). Theresidue was cooled in an ice bath and basified by the careful additionof saturated, aqueous sodium bicarbonate (100 ml). The product wasextracted into chloroform (2×100 ml), the organic phases combined, dried(Na₂ SO₄) and evaporated to residue under reduced pressure.Chromatography on alumina with ethyl acetate then ethyl acetate:methanol(9:1) gave a 1:1 mixture of diastereomers (2.1 g, 40%). δ_(H) [(CD₃)₂CO]1.0-1.3 (m, CH₃ CH and CH₃ CH.sub. 2), 1.65 (m, 5-CH₂), 2.0 (m,4-CH), 3.0-4.5 (m, 2-, 6-, 7-CH₂ and 3-CH), 4.1 (2 x q, CH₂ O), 6.69 (2x q, CH), 7.4-9.5 (m, naphthyl).

EXAMPLE 15 Ethyl (3R,4S)-1-azabicyclo[2.2.1]heptane-3-carboxylateoxalate (I, R=Et, x=zero)

Ethyl1-[(S)-1-phenylethyl]-(3R,4S)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide (4.8 g, 13.5 mmoles) in ethanol (200 ml) containing acetic acid(3 ml) was shaken with 10% palladium on carbon (0.6 g) under a hydrogenatmosphere (150 psi) for 48 hours at 20° C. The catalyst was removed byfiltration and washed with ethanol (3×50 ml). The combined filtrateswere evaporated to residue under reduced pressure at ≧40° C. The solidresidue was cooled in an ice-bath and basified by addition of saturatedaqueous sodium bicarbonate (20 ml). Chloroform (100 ml) was added,followed by sufficient water (10 ml) to give two clear layers. Thelayers were separated and the aqueous phase extracted with chloroform(2×100 ml). The combined extracts were dried (Na₂ SO₄), evaporated toresidue under reduced pressure, and flushed with isopropanol (20 ml). Asolution of anhydrous oxalic acid (1.22 g, 13.5 mmoles) in isopropanol(20 ml) was added and the mixture heated to give a clear solution. Thesolution was allowed to cool and crystallise at room temperature, thenaged at 5° C. for 1 hour. The solid was filtered, washed with coldisopropanol (2×10 ml), and dried in a vacuum at 40° C. to give theoxalate salt as a colourless crystalline solid (2.9 g, 84%), m.p.130°-132° C. (Found: C, 50.81; H, 6.59; N, 5.42. C₉ H₁₅ NO₂.C₂ H₂ O₄requires C, 50.96; H, 6.61; N, 5.40%); [α]_(D) -32° (c 0.5 in EtOH);δ_(C) (free base in (CD₃)₂ CO) 13.52, 59.67 (CH₃ CH₂ O), 24.88 (5-CH₂),40.72 (4-CH), 46.12 (3-CH), 53.25 (6-CH₂), 55.86 (7-CH₂), 59.67 (2-CH₂),173.64 (CO).

EXAMPLE 16 Ethyl (3S,4R)-1-azabicyclo[2.2.1]heptane-3-carboxylatehydrobromide (I, R=Et, x=zero)

Ethyl1-[(R)-1-phenylethyl]-(3S,4R)-1-azoniabicyclo[2.2.1]heptane-3-carboxylatebromide (600 g, 1.69 moles) and cyclohexene (2.4 l) in ethanol (15 l)were heated with 10% palladium on charcoal (60 g) at reflux temperaturefor 18 hours. The slurry was cooled to 20° C. and filtered. Theapparatus was rinsed with ethanol (2×1 l) and the filtrates combined andevaporated to residue in vacuo to give the hydrobromide salt as acolourless crystalline solid (400 g, 94%), m.p. 168°-170° C. (Found: C,43.35, H, 6.40; N, 5.55. C₉ H₁₅ NO₂.HBr requires C, 43.21; H, 6.45; N,5.60%); [α]_(D) +30.1° (c 0.5 in EtOH); δ_(C) (CD₃ OD) 12.54 (CH₃),22.55 (5-CH₂), 38.50 (4-CH), 43.09 (3-CH), 51.70 (6-CH₂), 53.58 (7-CH₂),60.77 (CH₂ O), 169.94 (CO).

EXAMPLE 17 endo (3S,4R)-1-Azabicyclo[2.2.1]heptane-3-carboxylic acid,hydrobromide (1, R=H, x=zero)

endo Ethyl (3S,4R)-1-azabicyclo[2.2.1]heptane-3-carboxylate hydrobromide(840 g, 3.36 moles) in concentrated hydrochloric acid (5.3 l) was heatedunder reflux for 5 hours and allowed to cool to room temperatureovernight. The solution was evaporated and the residue dried in vacuoover phosphorus pentoxide to give the acid hydrobromide salt as a solid(688 g, 92%), m.p. 230°-233° C. [α]_(D) +28.8° (c l in MeOH); δ_(C) (CD₃OD) 22.54 (5CH₂), 38.36 (4-CH), 42.97 (3-CH), 51.63 (6-CH₂), 53.63(7-CH₂), 59.67 (2-CH₂), 171.14 (CO).

We claim:
 1. A substantially pure enantiomer of formula (I): ##STR11##in exo-, endo- or a mixture of exo- and endo- forms; wherein x is 0 to1, and CO₂ R represents a carboxylic acid group, salt or reactivederivative thereof.
 2. The compound according to claim 1, wherein x iszero.
 3. The compound according to claim or 2, wherein R is C₁₋₄ alkyl.4. The compound according to claim 3, wherein R is ethyl.
 5. Thecompound according to claim 1 represented as ethyl(3R,4S)-1-azabicyclo[2.2.1]heptane-3-carboxylate.
 6. The compoundaccording to claim 1 represented asethyl(3S,4R)-1-azabicyclo[2.2.1]heptane-3-carboxylate hydrobromide. 7.The compound according to claim 1 represented as endo(3S,4R)-1-azabicyclo[2.2.1]heptane-3-carboxylic acid hydrobromide.